U.S. patent number 10,067,082 [Application Number 15/197,187] was granted by the patent office on 2018-09-04 for biosensor for determining an analyte concentration.
This patent grant is currently assigned to Ascensia Diabetes Care Holdings AG. The grantee listed for this patent is Ascensia Diabetes Care Holdings AG. Invention is credited to Greg P. Beer, Huan-Ping Wu, Kin-Fai Yip.
United States Patent |
10,067,082 |
Beer , et al. |
September 4, 2018 |
Biosensor for determining an analyte concentration
Abstract
A biosensor (102) for determining the presence or amount of a
substance in a sample and methods of use of the biosensor (102) are
provided. The biosensor (102) for receiving a user sample to be
analyzed includes a mixture for electrochemical reaction with an
analyte. The mixture includes an enzyme, a mediator and an
oxidizable species as an internal reference.
Inventors: |
Beer; Greg P. (Fairfield,
CA), Wu; Huan-Ping (Granger, IN), Yip; Kin-Fai
(Pittsburgh, PA) |
Applicant: |
Name |
City |
State |
Country |
Type |
Ascensia Diabetes Care Holdings AG |
Basel |
N/A |
CH |
|
|
Assignee: |
Ascensia Diabetes Care Holdings
AG (Basel, CH)
|
Family
ID: |
34860292 |
Appl.
No.: |
15/197,187 |
Filed: |
June 29, 2016 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20160313272 A1 |
Oct 27, 2016 |
|
Related U.S. Patent Documents
|
|
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|
|
|
|
Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
14193214 |
Feb 28, 2014 |
9410917 |
|
|
|
10590765 |
Apr 15, 2014 |
8696880 |
|
|
|
PCT/US2005/003622 |
Feb 4, 2005 |
|
|
|
|
60542362 |
Feb 6, 2004 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
G01N
27/3274 (20130101); C12Q 1/004 (20130101); G01N
33/54373 (20130101); G01N 27/3273 (20130101); G01N
27/3271 (20130101); C12Q 1/006 (20130101); G01N
27/3272 (20130101) |
Current International
Class: |
G01N
33/487 (20060101); G01N 27/327 (20060101); C12Q
1/00 (20060101); G01N 33/543 (20060101) |
Field of
Search: |
;204/403.01-403.15
;205/777.5 |
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|
Primary Examiner: Slawski; Magali P
Assistant Examiner: Carlson; Kourtney R S
Attorney, Agent or Firm: Nixon Peabody LLP
Parent Case Text
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation of application Ser. No.
14/193,214 filed Feb. 28, 2014, which has been allowed; application
Ser. No. 14/193,214 filed Feb. 28, 2014 is a division of
application Ser. No. 10/590,867 filed Aug. 24, 2006, which has
issued as U.S. Pat. No. 8,696,880; application Ser. No. 10/590,867
filed Aug. 24, 2006 is a nationalized application of Application
No. PCT/US2005/03622 filed Feb. 4, 2005, which claims priority to
Application No. 60/542,362 filed on Feb. 6, 2004, which are all
incorporated by reference in their entireties.
Claims
What is claimed is:
1. A biosensor for determination of an analyte concentration in a
fluid sample, the biosensor comprising: a working electrode; a
counter electrode; and a mixture for electrochemical reaction with
an analyte, the mixture including the enzyme, a mediator, and an
oxidizable species as an internal reference, the mediator being
ferricyanide, the oxidizable species being ferrocyanide, the
ferrocyanide being from 0.1 to 1% of the total ferricyanide, the
mixture being located as a single layer directly on a surface of at
least a portion of the working electrode prior to the introduction
of the fluid sample, the mixture including only one enzyme.
2. The biosensor of claim 1, wherein the enzyme comprises glucose
oxidase.
3. The biosensor of claim 1, wherein the mixture is located as a
single layer directly on a surface of at least a portion of the
counter electrode prior to the introduction of the fluid
sample.
4. A method of forming and applying a reagent mixture for an
electrochemical reaction with an analyte of a fluid sample in a
biosensor, the biosensor having a working electrode and a counter
electrode, the method the acts of comprising: forming a batch of
the reagent mixture by adding an enzyme, adding a mediator and
adding a known amount of an oxidizable species, the added
oxidizable species being added separately from the mediator, the
mediator being ferricyanide, the oxidizable species being
ferrocyanide; and after forming the reagent mixture, placing the
reagent mixture directly on a surface of at least a portion of the
working electrode of the biosensor prior to the introduction of the
fluid sample, the mixture including only one enzyme.
5. The method of claim 4, wherein the enzyme comprises glucose
oxidase.
6. The method of claim 4, wherein the mixture is located as a
single layer directly on a surface of at least a portion of the
counter electrode prior to the introduction of the fluid
sample.
7. A method of using a biosensor to assist in determining glucose
concentration of a fluid sample, the method comprising: providing a
biosensor including a working electrode, a counter electrode and a
reagent, the reagent located directly on a surface of at least a
portion of the working electrode prior to introduction of the test
sample, the reagent including an enzyme, a mediator and an
oxidizable species as an internal reference, the mediator being
ferricyanide, the oxidizable species being ferrocyanide, the
ferrocyanide being from 0.1 to 1% of the total ferricyanide;
applying a first voltage potential in a first voltage period;
providing a set delay period; and applying a second voltage
potential in a second voltage period following the delay
period.
8. The method of claim 7, wherein the enzyme comprises glucose
oxidase.
9. The method of claim 7, wherein the mixture is located as a
single layer directly on a surface of at least a portion of the
counter electrode prior to the introduction of the fluid sample.
Description
FIELD OF THE INVENTION
The present invention generally relates to a biosensor, and, more
particularly, to a new and improved biosensor, including an
oxidizable species as an internal reference and methods of use of
the biosensor, for determining the presence or amount of a
substance in a sample.
DESCRIPTION OF THE PRIOR ART
The quantitative determination of analytes in body fluids is of
great importance in the diagnoses and maintenance of certain
physiological abnormalities. For example lactate, cholesterol and
bilirubin should be monitored in certain individuals. In
particular, the determination of glucose in body fluids is of great
importance to diabetic individuals who must frequently check the
level of glucose in their body fluids as a means of regulating the
glucose intake in their diets. While the remainder of the
disclosure herein will be directed towards the determination of
glucose, it is to be understood that the new and improved sensor
element and method of use of this invention can be used for the
determination of other analytes upon selection of the appropriate
enzyme.
Methods for determining analyte concentration in fluids can be
based on the electrochemical reaction between the analyte and an
enzyme specific to the analyte and a mediator which maintains the
enzyme in its initial oxidation state. Suitable redox enzymes
include oxidases, dehydrogenases, catalase and peroxidase. For
example, in the case where glucose is the analyte, the reaction
with glucose oxidase and oxygen is represented by equation:
##STR00001##
In the initial step of the reaction represented by equation (A),
glucose present in the test sample converts the enzyme (E.sub.ox),
such as the oxidized flavin adenine dinucleotide (FAD) center of
the enzyme into its reduced form (E.sub.red), for example,
(FADH.sub.2). Because these redox centers are essentially
electrically insulated within the enzyme molecule, direct electron
transfer to the surface of a conventional electrode does not occur
to any measurable degree in the absence of an unacceptably high
cell voltage. An improvement to this system involves the use of a
nonphysiological redox coupling between the electrode and the
enzyme to shuttle electrons between the (FADH.sub.2) and the
electrode. This is represented by the following scheme in which the
redox coupler, typically referred to as a mediator, is represented
by M: Glucose+GO(FAD).fwdarw.gluconolactone+GO(FADH.sub.2)
GO(FADH.sub.2)+2M.sub.ox.fwdarw.GO(FAD)+2M.sub.red+2H.sup.+
2M.sub.red.fwdarw.2M.sub.ox+2e.sup.-(at the electrode)
In the scheme, GO(FAD) represents the oxidized form of glucose
oxidase and GO(FAD H.sub.2) indicates its reduced form. The
mediating species M.sub.ox/M.sub.red shuttles electrons from the
reduced enzyme to the electrode thereby oxidizing the enzyme
causing its regeneration in situ.
U.S. Pat. Nos. 5,620,579 and 5,653,863 issued to Genshaw et al.,
and assigned to the present assignee, disclose apparatus and method
for determining the concentration of an analyte in a fluid test
sample by applying the fluid test sample to the surface of a
working electrode, which is electrochemically connected to a
counter electrode, and which surface bears a composition comprising
an enzyme specific for the analyte. A mediator is reduced in
response to a reaction between the analyte and the enzyme. An
oxidizing potential is applied between the electrodes to return at
least a portion of the mediator back to its oxidized form before
determining the concentration of the analyte to thereby increase
the accuracy of the analyte determination. Following this initially
applied potential, the circuit is switched to an open circuit or to
a potential that substantially reduces the current to minimize the
rate of electrochemical potential at the working electrode. A
second potential is applied between the electrodes and the current
generated in the fluid test sample is measured to determine analyte
concentration. Optionally, the accuracy of the analyte
determination is further enhanced algorithmically.
SUMMARY OF THE INVENTION
Important aspects of the present invention are to provide a new and
improved biosensor for determining the presence or amount of a
substance in a sample including an oxidizable species as an
internal reference and method of use of the biosensor.
In brief, a biosensor for determining the presence or amount of a
substance in a sample and methods of use of the biosensor are
provided. The biosensor for receiving a user sample to be analyzed
includes a mixture for electrochemical reaction with an analyte.
The mixture includes an enzyme, a mediator and an oxidizable
species as an internal reference.
The internal reference is defined as the oxidizable species which
in one embodiment can be further defined as the reduced form of a
reversible redox couple that has an equal or higher redox potential
than that of the mediator. The internal reference acts to increase
the response current additively for operation potentials that
oxidize both species and in the case where glucose is the analyte,
a total response current is represented by:
I.sub.total=I.sub.int-ref+I.sub.glucose
I.sub.int-ref.varies.(internal reference) and
I.sub.glucose.varies.(glucose); Where I.sub.int-ref is the portion
of the total response current due to the internal reference, while
I.sub.glucose is due to the oxidation of mediator proportional to
the glucose concentration.
In accordance with features of the invention, the internal
reference can be either the same mediator species or an oxidizable
species with a higher redox potential than the mediator. Thus for
biosensors with a low operation potential oxidizing only the
mediator, the current I.sub.int-ref will be zero. However, for
biosensors with a higher operation potential that oxidizes both
species, the total response current will be the sum of the portion
due to internal reference and that due to glucose. Since the
internal reference concentration is fixed, the calibration slope of
the sensor will only depend on the sensor response for glucose
while the intercept will depend on the added amount of the internal
reference. In another words, the internal reference will only
offset the intercept and will not change the calibration slope.
Thus, the concept of internal reference provides new and different
ways to make glucose biosensors.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention together with the above and other objects and
advantages may best be understood from the following detailed
description of the preferred embodiments of the invention
illustrated in the drawings, wherein:
FIG. 1A is a block diagram representation of biosensor meter
including a biosensor having an internal reference in accordance
with the present invention;
FIGS. 1B, 1C, and 1D are diagrams respectively illustrating
operational methods for use with the biosensor of FIG. 1 of the
invention;
FIGS. 2A, 2B, and 2C are charts showing three cyclic voltammograms
of MLB based glucose biosensors with ferrocyanide as the internal
reference the biosensor of FIG. 1 of the invention in whole blood
samples of 0 mg/dL glucose;
FIG. 3 is a chart illustrating a linear response of the biosensor
of FIG. 1 of the invention at different voltage operating
potentials;
FIG. 4 is a chart illustrating effect of the added internal
reference to the overall voltammetric current using biosensors of
FIG. 1 of the invention with 10% printed ferricyanide as the
counter electrode;
FIGS. 5A and 5B are charts illustrating linear response and
increased intercept with increasing internal reference of MLB based
biosensors of FIG. 1 of the invention with Ag/AgCl as the counter
electrode;
FIGS. 6A and 6B are charts illustrating linear response and
increased intercept with increasing internal reference of MLB based
biosensors of FIG. 1 of the invention with 10% ferricyanide as the
counter electrode;
FIG. 7 is a chart illustrating linear relationship of the
calibration intercept with increasing internal reference of DEX
biosensors of FIG. 1 of the invention with 10% ferricyanide as the
counter electrode; and
FIGS. 8A and 8B are charts illustrating the ratio of signal to
reference results from flow-injection-analysis (FIA) of the
residual ferrocyanide from a control reagent ink and the reagent
ink with 0.1% ferrocyanide added to the reagent mixture of 20%
ferricyanide of a biosensor of FIG. 1 of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention relates to an electrochemical biosensor for
determining the presence or amount of a substance in a sample. The
biosensor includes sensor strips containing a working electrode and
a counter electrode, each of which is at least partially covered
with, for example, a separate reagent layer. The reagent layer on
the working electrode includes, for example, an enzyme that
interacts with an analyte through an oxidation-reduction reaction
and also includes a mediator that is the oxidized form of a redox
couple. The biosensor of the invention includes an internal
reference or a reduced form of the mediator in the reagent layer on
the working electrode. The internal reference is defined as an
oxidizable species which in one embodiment can be further defined
as a reduced form of a reversible redox couple that has an equal or
higher redox potential than that of the mediator. A fixed
quantitative amount of the internal reference is provided in the
reagent layer. The biosensors of the invention including the
internal reference or added amount of the reduced form of mediator
provide for improvements in that the internal reference acts to
anchor the calibration intercept by nature of thermodynamics while
maintaining the calibration slope.
Many compounds are useful as mediators due to their ability to
accept electrons from the reduced enzyme and transfer them to the
electrode. A necessary attribute of a mediator is the ability to
remain in the oxidized state under the conditions present on the
electrode surface prior to the use of the sensor. Among the more
venerable mediators are the oxidized form of organometallic
compounds, organic molecules, transition metal coordination
complexes. A specific example of mediator is the potassium
hexacyanoferrate (III), also known as ferricyanide.
As used in the following specification and claims, the term
biosensor means an electrochemical sensor strip or sensor element
of an analytical device or an instrument that responds selectively
to analytes in an appropriate sample and converts their
concentration into an electrical signal. The biosensor generates an
electrical signal directly, facilitating a simple instrument
design. Also, a biosensor offers the advantage of low material cost
since a thin layer of chemicals is deposited on the electrodes and
little material is wasted.
The term "sample" is defined as a composition containing an unknown
amount of the analyte of interest. Typically, a sample for
electrochemical analysis is in liquid form, and preferably the
sample is an aqueous mixture. A sample may be a biological sample,
such as blood, urine or saliva. A sample may be a derivative of a
biological sample, such as an extract, a dilution, a filtrate, or a
reconstituted precipitate.
The term "analyte" is defined as a substance in a sample, the
presence or amount of which is to be determined. An analyte
interacts with the oxidoreductase enzyme present during the
analysis, and can be a substrate for the oxidoreductase, a
coenzyme, or another substance that affects the interaction between
the oxidoreductase and its substrate.
The term "oxidoreductase" is defined as any enzyme that facilitates
the oxidation or reduction of a substrate. The term oxidoreductase
includes "oxidases," which facilitate oxidation reactions in which
molecular oxygen is the electron acceptor; "reductases," which
facilitate reduction reactions in which the analyte is reduced and
molecular oxygen is not the analyte; and "dehydrogenases," which
facilitate oxidation reactions in which molecular oxygen is not the
electron acceptor. See, for example, Oxford Dictionary of
Biochemistry and Molecular Biology, Revised Edition, A. D. Smith,
Ed., New York: Oxford University Press (1997) pp. 161, 476, 477,
and 560.
The term "oxidation-reduction" reaction is defined as a chemical
reaction between two species involving the transfer of at least one
electron from one species to the other species. This type of
reaction is also referred to as a "redox reaction." The oxidation
portion of the reaction involves the loss of at least one electron
by one of the species, and the reduction portion involves the
addition of at least one electron to the other species. The ionic
charge of a species that is oxidized is made more positive by an
amount equal to the number of electrons transferred. Likewise, the
ionic charge of a species that is reduced is made less positive by
an amount equal to the number of electrons transferred.
The term "oxidation number" is defined as the formal ionic charge
of a chemical species, such as an atom. A higher oxidation number,
such as (III), is more positive, and a lower oxidation number, such
as (II), is less positive. A neutral species has an ionic charge of
zero. Oxidation of a species results in an increase in the
oxidation number of that species, and reduction of a species
results in a decrease in the oxidation number of that species.
The term "redox pair" is defined as two species of a chemical
substance having different oxidation numbers. Reduction of the
species having the higher oxidation number produces the species
having the lower oxidation number. Alternatively, oxidation of the
species having the lower oxidation number produces the species
having the higher oxidation number.
The term "oxidizable species" is defined as the species of a redox
pair having the lower oxidation number, and which is thus capable
of being oxidized into the species having the higher oxidation
number. Likewise, the term "reducible species" is defined as the
species of a redox pair having the higher oxidation number, and
which is thus capable of being reduced into the species having the
lower oxidation number.
The term "organotransition metal complex," also referred to as "OTM
complex," is defined as a complex where a transition metal is
bonded to at least one carbon atom through a sigma bond (formal
charge of -1 on the carbon atom sigma bonded to the transition
metal) or a pi bond (formal charge of 0 on the carbon atoms pi
bonded to the transition metal). For example, ferrocene is an OTM
complex with two cyclopentadienyl (Cp) rings, each bonded through
its five carbon atoms to an iron center by two pi bonds and one
sigma bond. Another example of an OTM complex is ferricyanide (III)
and its reduced ferrocyanide (II) counterpart, where six cyano
ligands (formal charge of -1 on each of the 6 ligands) are sigma
bonded to an iron center through the carbon atoms of the cyano
groups.
The term "coordination complex" is defined as a complex having
well-defined coordination geometry, such as octahedral or square
planar geometry. Unlike OTM complexes, which are defined by their
bonding, coordination complexes are defined by their geometry.
Thus, coordination complexes may be OTM complexes (such as the
previously mentioned ferricyanide), or complexes where non-metal
atoms other than carbon, such as heteroatoms including nitrogen,
sulfur, oxygen, and phosphorous, are datively bonded to the
transition metal center. For example, ruthenium hexaamine, or
hexaaminoruthenate (II)/(III), is a coordination complex having a
well-defined octahedral geometry where six NH.sub.3 ligands (formal
charge of 0 on each of the 6 ligands) are datively bonded to the
ruthenium center. Ferricyanide is also an example of the
coordination complex that has the octahedral geometry. A more
complete discussion of organotransition metal complexes,
coordination complexes, and transition metal bonding may be found
in Collman et al., Principles and Applications of Organotransition
Metal Chemistry (1987) and Miessler & Tarr, Inorganic Chemistry
(1991).
The term "mediator" is defined as a substance that can be oxidized
or reduced and that can transfer one or more electrons between a
first substance and a second substance. A mediator is a reagent in
an electrochemical analysis and is not the analyte of interest. In
a simplistic system, the mediator undergoes a redox reaction with
the oxidoreductase after the oxidoreductase has been reduced or
oxidized through its contact with an appropriate substrate. This
oxidized or reduced mediator then undergoes the opposite reaction
at the electrode and is regenerated to its original oxidation
number.
The term "electroactive organic molecule" is defined as an organic
molecule that does not contain a metal and that is capable of
undergoing an oxidation or reduction reaction. Electroactive
organic molecules can behave as redox species and as mediators.
Examples of electroactive organic molecules include coenzyme
pyrroloquinoline quinone (PQQ), benzoquinones and naphthoquinones,
N-oxides, nitroso compounds, hydroxylamines, oxines, flavins,
phenazines, phenothiazines, indophenols, and indamines.
The term "electrode" is defined as an electrically conductive
substance that remains stationary during an electrochemical
analysis. Examples of electrode materials include solid metals,
metal pastes, conductive carbon, conductive carbon pastes, and
conductive polymers.
Having reference now to the drawings, in FIG. 1 there is
illustrated a biosensor meter designated as a whole by the
reference character 100 of the preferred embodiment and arranged in
accordance with principles of the present invention. Biosensor
meter 100 includes a biosensor 102 arranged in accordance with
principles of the present invention. Biosensor meter 100 includes
microprocessor 104 together with an associated memory 106 for
storing program and user data. Digital data from the microprocessor
104 is applied to a digital-to-analog (D/A) converter 108. D/A
converter 108 converts the digital data to an analog signal. An
amplifier 110 coupled to the D/A converter 108 amplifies the analog
signal. The amplified analog signal output of amplifier 110 is
applied to the biosensor 102 of the invention. Biosensor 102 is
coupled to an amplifier 112. The amplified sensed signal is applied
to an analog-to-digital (A/D) converter 114 that converts the
amplified, analog sensor signal to a digital signal. The digital
signal is applied to the microprocessor 104.
Most of the commercially available disposable biosensors used for
monitoring blood glucose require the deposition/printing of a
mixture of an enzyme and a mediator with some binding agent. For
the application of glucose measurement, the mediator is in the
oxidized form of a redox couple. Depending on the redox couple, the
mediator can be a very strong oxidant, such as ferricyanide,
thereby chemically oxidizing the functional groups after mixing
with the enzyme and the binding agent. Subsequently, a small amount
of the reduced mediator is formed as impurity in the reagent in the
processes of ink mixing, storage and printing. Thus, the end result
of mixing and printing the reagent ink is the generation of the
reduced form of the redox couple, giving rise to the background
current. The formation of this reduced form of the mediator and
thus the background current may vary from batch to batch. This
process-generated reduced form of the mediator, such as
ferrocyanide from ferricyanide, can be oxidized in general to
minimize the background signal using the algorithm outlined in the
U.S. Pat. Nos. 5,620,579 and 5,653,863, to Genshaw et al., and
assigned to the present assignee. However, the process-dependent
background signal, which is translated into the calibration
intercept, can be spread out in a range of values. At the extremes
of these diverged values of intercept, analytical accuracy will be
suffered because no reasonable calibration intercept can be
assigned to accommodate the diverged intercept.
In accordance with features of the invention, a grade of mediator
that contains a certain level of the reduced form of the mediator
in the reagent is used for decreasing the effect of the strong
oxidant. Thermodynamically, the presence of a small amount of the
reduced form of the mediator in the ink mixture of enzyme and
mediator decreases the driving force for the conversion from the
oxidized to the reduced form. This is advantageously accomplished
by adding a small fixed amount of the reduced form of the mediator
to the oxidized mediator.
Even though background signal will be generated, the algorithm in
the U.S. Pat. Nos. 5,620,579 and 5,653,863 will minimize the effect
of background to increase the accuracy of the glucose sensor. The
above-identified patents disclose a method that reduces the
background bias due to oxidizable impurities in an amperometric
sensor used for measuring a specific analyte, such as glucose, in
blood. The background current of such a sensor will increase if it
is stored over a long period of time or under stress (heat,
moisture, etc.) due to the increased presence of reduced mediator
or other reduced impurity present in the sensor such as enzyme
stabilizers, e.g. glutamate, and surfactants having reducing
equivalents. For example, in a ferricyanide based amperometric
sensor, the background bias is related to the presence of
ferrocyanide (from the reduction of ferricyanide) near the
electrode surface. This accumulated ferrocyanide, as opposed to the
ferrocyanide produced during use of the sensor (fresh
ferrocyanide), is oxidized back to ferricyanide to reduce the
background bias it causes and thereby extend the sensor shelf life.
To achieve this objective, the method uses an electrochemical
approach. The background bias is further reduced when the
electrochemical approach is augmented with an algorithmic
correction.
The disclosed method involves first applying a positive potential
pulse (called the "burn-off" pulse) which precedes the normal
potential profile during use of the biosensor. This is typically
accomplished by applying a positive potential of from 0.1 to 0.9
volt (preferably 0.3 to 0.7 volt) between the working and reference
electrodes of the sensor for a period of from 1 to 15 seconds
(preferably 5 to 10 seconds). The burn-off pulse oxidizes the
initial ferrocyanide (or other oxidizable impurity), so that the
sensor can begin the assay with a clean background. Typically, the
background is not perfectly clean since only a portion of the
oxidizable impurity is oxidized by the burn-off pulse. This is the
case because the chemical layer covers both the working and the
counter electrodes. The initial ferrocyanide exists in the chemical
layer since it comes from ferricyanide. When sample fluid is
applied and the chemical layer re-hydrates, the ferrocyanide near
the working electrode is re-oxidized. The rest of the ferrocyanide
diffuses into the sample fluid and is mixed with the glucose. That
portion of the initial ferrocyanide cannot be re-oxidized without
affecting the glucose. The initial ferrocyanide is near the
electrode for a very short time (a few seconds) after the fluid
test sample is applied. The reason for this is that the chemicals
(enzyme and ferricyanide, etc.) are deposited as a thin layer on
the working and counter electrodes. The burn-off technique takes
advantage of this since a significant amount of the initial
ferrocyanide can be burned off without noticeable reduction of the
analyte concentration in the fluid test sample most of which does
not come into direct contact with the electrode. Experiments have
demonstrated that the background bias of a stressed sensor can be
reduced by 40% with proper application of the burn-off pulse.
The disclosed method of the U.S. Pat. Nos. 5,620,579 and 5,653,863
advantageously is applied to minimize the effect of background
signal to increase the accuracy of the glucose biosensor meter 100
of the preferred embodiment. The subject matter of the
above-identified patents is incorporated herein by reference.
In accordance with features of the invention, the added amount of
the reduced form of mediator acts to anchor the calibration
intercept by nature of thermodynamics while maintaining the
calibration slope. In light of the function the reduced form of
mediator, for example, ferrocyanide, plays in the glucose sensor,
it is referred to as the internal reference.
Examples of electroactive organic molecule mediators are described
in U.S. Pat. No. 5,520,786, issued to Bloczynski et al. on May 28,
1996, and assigned to the present assignee. In particular, a
disclosed mediator (compound 18 in TABLE 1) comprising
3-phenylimino-3H-phenothiazine referred to herein as MLB-92, has
been used to make a glucose biosensor 102 in accordance with
features of the invention. The subject matter of the
above-identified patent is incorporated herein by reference.
A commercially available biosensor meter and biosensor is
manufactured and sold by Bayer Corporation under the trademark
Ascensia DEX. The Ascensia DEX biosensor includes generally as pure
a form of ferricyanide as possible for the reagent. The Ascensia
DEX biosensor has been used to make a glucose biosensor 102 in
accordance with features of the invention by adding an adequate
amount of ferrocyanide to the pure ferricyanide. Benefits of adding
ferrocyanide defining the internal reference of biosensor 102 to
the Ascensia DEX reagent ink include an immediate benefit of
increasing the intercept without changing slope, anchoring the
intercept range, and increasing long-term stability of biosensor
during storage.
In accordance with features of the invention, the MLB-92 mediator
having a lower redox potential was used to make a glucose biosensor
102 with special properties. With the addition of adequate amounts
of the internal reference, ferrocyanide, the new biosensor system
can be made to work with two operation potentials: (1) at 400 mV
where both the new mediator and the internal reference are
oxidized, and (2) at 100 mV where only the new mediator can be
oxidized. The significance of this approach is two-fold. First, the
glucose biosensor 102 such formulated (new mediator and internal
reference) can be operated at a high potential (+400 mV) to produce
currents in a range that fits the calibration characteristics of
the hardware requirements of the existing instrument. Secondly,
since the lower redox potential and thus a lower oxidation power of
the mediator will likely to have virtually no conversion of the
oxidized form to the reduced form of the mediator, a lower
operation potential (0-100 mV) can be applied to the sensor so as
to avoid the oxidation of the internal reference. Thus, a new set
of calibration characteristics based on the new mediator, most
likely with near zero intercept due to the lower oxidation power,
will lead to a better analytical precision for glucose
measurements. It will also reduce the matrix interference in the
whole blood by avoiding the oxidation of some of the known
oxidizable species such as uric acid and acetaminophen.
In accordance with features of the invention, another application
of the internal reference to glucose sensors 102 is to add
adequately large amount of internal reference to the biosensor
system to produce a high current response. Using the double steps
algorithm with open circuit between them (Bayer U.S. Pat. Nos.
5,620,579 and 5,653,863), the first potential step is set at 400 mV
to produce a current that is mostly due to the internal reference
signal while the second step is set at a low potential (0-100 mV)
to produce a current signal related to the glucose concentration
only. The ratio of the first signal, which should be virtually
independent of the whole blood hematocrit, to the second signal at
low potential can be used to correct for the analytical bias due to
hematocrit effect.
In accordance with features of the invention, the internal
reference is defined as the oxidizable species which in one
embodiment is further defined as the reduced form of a reversible
redox couple that has an equal or higher redox potential than that
of the mediator. The concept and use of an internal reference are
very common in the field of analytical chemistry. However, no
example of using an internal reference for biosensors has been
suggested in existing patents or literature. In all three scenarios
described above, the internal reference acts to increase the
response current additively for operation potentials that oxidize
both species and with glucose as the analyte; a total response
current is represented by: I.sub.total=I.sub.int-ref+I.sub.glucose
I.sub.int-ref.varies.(internal reference) and
I.sub.glucose.varies.(glucose); Where I.sub.int-ref is the portion
of the total response current due to the internal reference, while
I.sub.glucose is due to the oxidation of mediator proportional to
the glucose concentration.
In accordance with features of the invention, the internal
reference can be either the same mediator species or an oxidizable
species with a higher redox potential than the mediator. Thus for
biosensors with a low operation potential oxidizing only the
mediator, the current I.sub.int-ref will be zero. However, for
biosensors with a higher operation potential that oxidizes both
species, the total response current will be the sum of the portion
due to internal reference and that due to glucose. Since the
internal reference concentration is fixed, the calibration slope of
the sensor will only depend on the sensor response for glucose
while the intercept will depend on the added amount of the internal
reference. In another words, the internal reference will only
offset the intercept and will not change the calibration slope.
Thus, the concept of internal reference provides new and different
ways to make glucose biosensors.
Referring now to FIGS. 1B, 1C, and 1D, there are at least three
modes of operation based on the use of internal reference for
glucose biosensors 102 of the invention. Potentiostatically, the
three of modes of operation are represented in FIGS. 1B, 1C, and
1D. Each of the illustrated modes of operation include a first
burnoff pulse, followed by a second wait period or open circuit,
and a final third read pulse, each pulse or period having a
selected duration, for example, 10 seconds. In the basic and most
immediate operation, ferrocyanide is retained in ferricyanide at
the concentration of 0.1 to 1% of the total ferricyanide providing
the internal reference for glucose biosensors 102 of the invention.
This is depicted in FIG. 1B where both potentials in the first and
the third periods are at the same voltage, for example 400 mV.
Retaining of a small percentage of ferrocyanide defining the
internal reference can be accomplished either by an appropriate
purification process of ferricyanide or by adding an adequate
amount of ferrocyanide to the pure ferricyanide. The outcome of
these retaining processes is to keep deliberately a desirable
amount of ferrocyanide in ferricyanide as a special grade of
ferricyanide. This is in contrast to the conventional wisdom of
having as pure a form of ferricyanide as possible, such as for the
DEX reagent, usually ferrocyanide in the order of 0.05% of
ferricyanide or less as impurity. The most desirable amount is 0.1%
ferrocyanide in the final formulation for DEX sensor, which will
lead to the anchoring of the calibration intercept at a narrower
range while maintaining the calibration slope for the DEX
sensor.
In FIG. 1C the second mode of operation is shown, where a desirable
amount of ferrocyanide (the internal reference) is added to the
reagent of enzyme and a mediator with a redox potential lower than
that of the internal reference. The biosensor 102 is expected to
work under high and low potentials (for example at 400 mV and 100
mV vs. Ag/AgCl) for existing instruments and instruments with a new
hardware requirement. This biosensor can be operated in potential
programs depicted in FIG. 1B for existing instruments 100 and FIG.
1C for new instruments 100. Examples of the mediator and internal
reference combination include the system of MLB-92 and ferrocyanide
as well as ruthenium hexaamine and ferrocyanide. The separation of
the two redox potentials is large enough so that there will be
generally no oxidation of the internal reference species when
operated at the low voltage.
In FIG. 1D the third mode of operation is shown, where a higher but
desirable concentration of ferrocyanide is added to the reagent
mixture of enzyme and a mediator with a redox potential lower than
that of the internal reference. The amount of the internal
reference would produce a current equivalent to about 50% to 75% of
the full scale in the calibration range preferably. In the
operation algorithm, the first potential step is set to oxidize
both the mediator and the internal reference (400 mV) while the
second potential step for the read pulse is to oxidize the mediator
only (0-100 mV). The current in the first potential step of FIG. 1D
will be most pertinent to the internal reference that is
immediately next to the electrode and should have virtually no
hematocrit effect. The ratio of the current from the second step to
that from the first step will provide a correction for the
analytical bias due to hematocrit effect.
Experiments have been carried out to show the feasibility of the
method of adding internal reference to a mediator system to
overcome existing problems or to enhance sensor performance in
accordance with the biosensor 102 of the invention.
Referring now to FIGS. 2A, 2B, and 2C, there are shown three cyclic
voltammograms illustrating operation of the biosensor 102 of the
invention. The illustrated three cyclic voltammograms are for MLB
based glucose biosensors 102 with ferrocyanide as the internal
reference in whole blood samples of 0 mg/dL glucose.
FIG. 2A illustrates working electrode vs. ferricyanide counter
electrode, FIG. 2B illustrates working electrode vs. silver (Ag)
and silver chloride (AgCl) or Ag/AgCl counter electrode and FIG. 2C
illustrates working electrode vs. MLB-92 counter electrode.
Respective peaks labeled 1 and 2 represent the oxidation of the
mediator MLB.sub.red (reduced form of MLB) and the internal
reference ferrocyanide respectively for all three voltammogram
plots. The oxidation peak for MLB.sub.red shifts along the
potential scale as the redox couple on the counter electrode
changes from ferricyanide to Ag/AgCl to MLB-92. However, it can be
seen that the relative position of the mediator MLB-92 to the
internal reference ferrocyanide is the same in all three
voltammogram plots of FIGS. 2A, 2B, and 2C.
Referring to FIG. 3, there shown in FIG. 3 is a chart illustrating
a linear response of the biosensor 102 of the invention at
different voltage operating potentials. The biosensor 102 is
operated at (1) 400 mV potential and (2) 150 mV potential. FIG. 3
illustrates the linear dose response of MLB-92 mediator based
biosensor 102 with 20 mM ferrocyanide as the internal reference.
Respective lines labeled EXAMPLE 1 and EXAMPLE 2 are from 400 mV
and 150 mV operation potentials against Ag/AgCl counter electrode.
As shown in FIG. 3, the biosensor 102 gives virtually the same
slope but with different intercepts for operations at 400 mV and
150 mV potentials. This result demonstrates that the internal
reference can be selectively oxidized or avoided by the operation
potential. Thus, one biosensor 102 can serve for two different
meters.
Examples of the biosensor 102 have been prepared systematically
showing the increase of intercept with increasing ferrocyanide as
the internal reference while the slopes were kept virtually
unchanged. Three working electrode reagents were prepared in the
following formulations. These three reagents were pin-deposited on
to two sensor formats: (1) Ag/AgCl as the counter electrode, (2)
10% printed ferricyanide as the counter electrode.
TABLE-US-00001 Enzyme, Internal PQQ- Mediator Reference Buffer and
Formulations GDH MLB-92 Ferricyanide binding agent, 1 20 unit/.mu.L
24 mM 0 mM 0.1M NaCl + phosphate, 1% CMC 2 20 unit/.mu.L 24 mM 4 mM
0.1M NaCl + phosphate, 1% CMC 3 20 unit/.mu.L 24 mM 8 mM 0.1M NaCl
+ phosphate, 1% CMC
FIG. 4 illustrates effect of the added internal reference to the
overall voltammetric current using biosensors 102 of the invention
with 10% printed ferricyanide as the counter electrode. FIG. 4
provides cyclic voltammograms of sensors with ferrocyanide as the
internal reference in whole blood samples of 0 mg/L glucose.
Voltammograms labeled A, B and C are with formulations 1, 2 and 3
respectively all with a counter electrode of 10% printed
ferricyanide.
The effect of the added internal reference to the overall
voltammetric current is shown in FIG. 4 using sensors with 10%
printed ferricyanide as the counter electrode. The main
oxidation/reduction peaks here are centered around -0.38 Volt vs.
10% ferricyanide, which is due to the mediator MLB. The oxidation
peak at about 0-50 mV is due to the internal reference of
ferrocyanide. While the oxidation peak for the internal reference
ferrocyanide increases with the increases of the internal reference
concentration from 0 to 4 to 8 mM, the oxidation peak for the
mediator is virtually unchanged. Here the concept of internal
reference is explained further by the fact that the main oxidation
peak of MLB.sub.red is unaffected by the presence of the internal
reference.
Referring to FIGS. 5A and 5B, charts illustrating linear response
and increased intercept with increasing internal reference of MLB
based biosensors 102 of the invention with Ag/AgCl as the counter
electrode are shown. FIG. 5A illustrates the linear dose response
of MLB based biosensors 102 with 0, 4, and 8 mM ferrocyanide,
respectively labeled EXAMPLE 1, EXAMPLE 2, and EXAMPLE 3. FIG. 5B
illustrates intercept and slope as a function of added ferrocyanide
in the working electrode reagent of the biosensor 102 of the
invention. All three sensors used Ag/AgCl as the counter
electrode.
Referring also to FIGS. 6A and 6B, charts illustrating linear
response and increased intercept with increasing internal reference
of MLB based biosensors 102 of the invention with 10% ferricyanide
as the counter electrode are shown. FIG. 6A illustrates the linear
dose response of MLB based biosensors 102 with 0, 4, and 8 mM
ferrocyanide, respectively labeled EXAMPLE 1, EXAMPLE 2, and
EXAMPLE 3. FIG. 6B illustrates intercept and slope as a function of
added ferrocyanide in the working electrode reagent of the
biosensor 102 of the invention. All three sensors used 10% printed
ferricyanide as the counter electrode.
In the dose response experiments, both sensor series with Ag/AgCl
counter electrode of FIGS. 5A and 5B, and 10% ferricyanide counter
electrode of FIGS. 6A and 6B show linear response and increased
intercept with increasing internal reference. For practical
purpose, the slope of the three sensors in FIGS. 5A and 5B is
unchanged while the intercept increases linearly with the added
ferrocyanide. The same linear relationship of intercept with added
ferrocyanide and the flat slope trend are repeated in sensor series
with the % printed ferricyanide as the counter electrode, as shown
in FIGS. 6A and 6B.
Experiments have been carried out to show the addition of
ferrocyanide to DEX reagent ink, modification of calibration
intercept without changing slope in accordance with the biosensor
102 of the invention.
FIG. 7 illustrates linear relationship of the calibration intercept
with increasing internal reference of DEX type biosensors 102 of
the invention. Five different formulations in a set format labeled
BC7 in FIG. 7 were made with 0, 0.02, 0.04, 0.06 and 0.08%
ferrocyanide mixed in the standard DEX reagent for the DEX sensor.
The regression slope and intercepts for these five sensors of the
BC7 format are shown in FIG. 7. Except for sensor with 0.06%
ferrocyanide due to the experimental problems, the intercepts of
the other four sensors give a nice linear function with respect to
the added amount of ferrocyanide as the internal reference. On the
other hand, the slopes of all five sensors fall in a flat line
indicating that the addition of the internal reference does not
change the slope of the DEX type biosensors 102 of the
invention.
FIGS. 8A and 8B illustrate the ratio of signal to reference results
from flow-injection-analysis (FIA) of the residual ferrocyanide
from a control reagent ink and the reagent ink with 0.1%
ferrocyanide added to the reagent mixture of 20% ferricyanide of a
biosensor 102 of the invention. One of the subtle effects of adding
the internal reference ferrocyanide to the DEX reagent ink is to
decrease the driving force for the conversion of the mediator
ferricyanide to ferrocyanide. Thus, ferricyanide becomes the source
of the residual current in the DEX sensor. One way of showing this
subtle effect is to monitor the increase of the residual current
(background current) of the reagent ink with internal reference
along with the control reagent ink over a long period of time. Both
reagent inks were stored in refrigeration (2-8.degree. C.) over
several weeks. FIG. 8 shows the results of FIA of the residual
ferrocyanide from both reagent inks. From FIG. 8, the ratio of
signal-to-reference (S/R) represents the relative amount of
ferrocyanide from the reagent ink compared to the added
ferrocyanide as the reference in FIA. Thus, the higher the value of
S/R from the FIA analysis, the higher the ferrocyanide in the
reagent inks. It can be seen from FIG. 8A that the S/R value
increase over the period of six weeks for both the control inks and
the reagent ink with added ferrocyanide. However, the reagent ink
curve with added ferrocyanide has a slower increase of residual
current over the period of six weeks compared to control curves. In
FIG. 8B, the S/R response curves from the control inks and the
reagent ink with added ferrocyanide are merged together for
comparison. To the first order approximation (since the
coefficients for the second order terms of both second order
polynomials are very small), the rate of residual current increase
over six weeks during refrigeration is about 30%
([0.0918-0.0638]/0.0918=30%) smaller for the reagent ink curve with
added ferrocyanide than for the control curves. Thus, it may be
understood from FIGS. 8A and 8B that the rate of the
ferricyanide-to-ferrocyanide conversion in reagent ink is decreased
substantially by the addition of the internal reference
ferrocyanide to the DEX reagent ink in accordance with biosensor
102 of the invention.
While the present invention has been described with reference to
the details of the embodiments of the invention shown in the
drawings, these details are not intended to limit the scope of the
invention as claimed in the appended claims.
* * * * *